System and method for treating kidney diseases in diabetic and non-diabetic patients

ABSTRACT

The present invention is a system and method capable of improving the entire metabolic process and through its multiplicity of effects on neurovascular reactivity, intraglomerular presure and hemodynamics, arresting the progression of overt diabetic nephropathy, improving intraglomerular hemodynamics, and thus arresting the progression of diabetic nephropathy and therefore reducing the risk of development of End Stage Renal Disease. The current system and method is for the treatment of kidney disease using insulin pulses to a patient utilizing Chronic Intermittent Intravenous Insulin Therapy to achieve the slowing, stopping or reversing of kidney disease in both diabetic and non-diabitic patient.

CROSS REFERENCE TO OTHER APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/212,132 filed Jun. 16, 2000.

FIELD OF INVENTION

[0002] This invention relates to the treatment of kidney disease indiabetic and non-diabetic patients. More specifically, the inventionrelates to a system and method for treating kidney disease in diabeticand non-diabetic patients with Chronic Intermittent Intravenous InsulinTherapy.

BACKGROUND OF THE INVENTION

[0003] Diabetic kidney disease (nephropathy) develops in 35 to 40% ofpatients with type 1 diabetes mellitus (DM) and in 10 to 60% of patientswith type 2 DM depending upon the ethnic pool being studied. It is themost common cause of End-Stage Renal Disease (ESRD) in the UnitedStates. Experts generally have assumed that diabetic nephropathy is theresult of hyperglycemia, whether alone or in combination with otherfactors, such as hypertension and genetic susceptibility to kidneydisease. Two major recent clinical trials involving patients with type 1DM (Diabetes Control and Complication Trial [DCCT]) and type 2 DM(United Kingdom Prospective Diabetes Study [UKPDS]) have demonstratedthat improved glycemic control reduces the onset and the progression ofearly diabetic nephropathy to overt nephropathy in patients recentlydiagnosed with diabetes mellitus (DM) thereby giving additional credenceto the hypothesis that a lack of glycemic control is the primary cause.Both of theses studies used recently diagnosed patients some of whom,although well controlled, went on to develop kidney disease. Since theDCCT and UKPDS studies demonstrated that near normalization of bloodglucose level did not always result in a delay of the onset orprogression of diabetic nephropathy, the hypothesis that euglycemia isthe means for addressing this disease, is made suspect.

[0004] Once nephropathy has become clinically overt (that is,macroalbuminuria and decreased glomerular filtration rate are detected),the degree of glycemic control is shown to have lost its importance as afactor. This provides additional evidence to refute the claim thatglycemic control is the primary factor to be addressed in kidneydisease, and that other mechanisms have greater overall influence.Indeed, most patients with DM and proteinuria eventually will progressto ESRD or premature death from cardiovascular complications. In suchpatients, with no medical intervention, the glomerular filtration ratedecreases an average of 1 ml/min per month, a deterioration that leadsto ESRD in a mean period of 7 years. Once overt persistent proteinuriais established, no known strategy exists that can stop or reverse theprogression to ESRD. Appropriate antihypertensive therapy has been shownto significantly reduce renal and possibly cardiovascular mortality inproteinuric type 1 DM patients, as well as retard the rate of decline ofglomerular filtration rate in some patients with impaired renal function(Lewis AJ et al, N Engl J Med 1993,329:1456-62). Thus, the standard ofcare for patients with diabetic nephropathy is intensive glycemiccontrol and normalization of the blood pressure using primarilyangiotensin converting enzyme inhibitors.

[0005] The pathophysiology of diabetic nephropathy is only partiallyunderstood. The most consistent morphologic finding in diabeticnephropathy is the enlargement of the mesangium, which can compress theglomerular capillaries and thus alter intraglomerular hemodynamics.McLennan et al (Diabetes, 1994,43:1041-45) showed that a high glucoseconcentration inhibits degradation of the mesangium and could promotethe mesangial enlargement observed in diabetic nephropathy.

[0006] The inventor hypothesizes that an improvement in the entiremetabolic milieu as observed with Chronic Intermittent IntravenousInsulin Therapy (CIIIT) could reverse the process discussed above andhave favorable effects on the progression of overt diabetic nephropathy.Furthermore, Chronic Intermittent Intravenous Insulin Therapy has beenshown to improve blood pressure control substantially and to reduce by46% the antihypertensive medication requirements in patients with type 1DM (Aoki TT et al, Diabetes Care, 1995,18:1260-65), possibly through animprovement in vascular reactivity. This effect was hypothesized by theinventor to favorably influence the intraglomerular hemodynamics anddelay the progression of diabetes-related renal disease.

[0007] What is needed is a system and method that improves the entiremetabolic process and through its multiplicity of effects onneurovascular reactivity, intraglomerular pressure and hemodynamics,could arrest the progression of overt diabetic nephropathy, improveintraglomerular hemodynamics, and thus arrest the progression ofdiabetic nephropathy and therefore reduce the risk of development ofESRD.

SUMMARY

[0008] Accordingly, the present invention is a system and method capableof improving the entire metabolic process and through its multiplicityof effects on neurovascular reactivity, intraglomerular pressure andhemodynamics, arresting the progression of overt diabetic nephropathy,improving intraglomerular hemodynamics, and thus arresting theprogression of diabetic nephropathy and therefore reducing the risk ofdevelopment of ESRD. The current invention is the treating of kidneydisease using insulin pulses to a patient utilizing Chronic IntermittentIntravenous Insulin Therapy to achieve the slowing, stopping orreversing of kidney disease in both diabetic and non-diabetic patients.One preferred embodiment of the invention is a system for treatingkidney disease in diabetic and non-diabetic patients through anintravenous administration of a pulse of insulin comprises a means fordetermining a respiratory quotient of a patient, a liquid or foodcontaining glucose, an intravenous site, and a means of delivering apulse of insulin at a regular interval of time.

[0009] In the preferred embodiment of the treatment system, anyinstrument capable of measuring the respiratory quotient determines arespiratory quotient of a patient. The respiratory quotient is definedas the ratio of carbon dioxide produced to oxygen consumed by thepatient. In the preferred embodiment, a liquid or food containingglucose is consumed by the patient to prevent hypoglycemia. Thepreferred liquid or food containing glucose is GLUCOLA, however anysimilar liquid or food containing glucose that will prevent hypoglycemiain the patient may be used.

[0010] The preferred means of delivering insulin is an infusion device.It is preferable that the infusion device is capable of providing pulsesof insulin on a prearranged interval, so long as there is sufficientglucose in the blood to keep the patient from becoming hypoglycemic. Thepreferred infusion device is also capable of delivering the pulses ofinsulin in as short duration of time as possible, without adverselyaffecting the vein at the site of infusion is used. However, lessaccurate devices may deliver the pulses and achieve the needed infusionprofile of approximately six minutes.

[0011] In the preferred embodiment, the intravenous site is a temporaryor permanent IV access site located in the body, forearm or hand of thepatient. The amount of insulin is tailored to achieve more normalmetabolic function of the kidney. Metabolic function is measured asstabilization or decrease in 24-hour urinary protein excretion orstabilization or increase in creatinine clearance. Type 1 diabeticpatients receive 20-35 milliunits of insulin per kilogram of body weightper pulse and type 2 diabetic patients receive 70-200 milliunits ofinsulin per kilogram of body weight per pulse. During periods ofnon-use, the IV site is preferably converted to a heparin or salinelock.

[0012] In one embodiment of the method of the invention, the patient isseated in a blood drawing chair and a 23 gauge needle/catheter isinserted into a hand or forearm vein to obtain vascular access. Althougha 23 gauge needle catheter is preferred, any system of such access mayaccomplish the needed result, including indwelling catheters. After ashort equilibration period, usually thirty minutes, the respiratoryquotient (the ratio of carbon dioxide produced to oxygen consumed by thepatient) of the patient is measured. The respiratory quotient measuringdevice may be any presently known model manufactured by any presentlyknown supplier of such instruments. In the preferred embodiment, thepatient is then asked to drink or eat liquid or food containing glucoseusually on the order of 60 to 100 grams of glucose. In the preferredembodiment a pulse of insulin is administered intravenously on a regularinterval of time, usually every six minutes, until the respiratoryquotient (RQ) shows improvement, as indicated by a respiratory quotientof 0.90 or greater. In the preferred embodiment, improvement in RQ isgenerally achieved within one hour. In the preferred embodiment, theinsulin/oral glucose phase is then followed by a rest period of usuallyone hour. In the preferred embodiment the entire procedure repeateduntil the desired effect is achieved.

[0013] The preferred method of insulin pulse delivery would be aprearranged interval, so long as there is sufficient glucose in theblood to keep the patient from becoming hypoglycemic. In order todetermine the progress of the patient, it is preferable the RQ ismeasured every hour and blood glucose levels are checked every 30minutes. The blood glucose level may be measured by any means whichshows that the patient is not becoming hypoglycemic. In the preferredembodiment, the patient is free to move around after the initial insulinpulses have been administered. In the preferred embodiment, theintravenous site is converted to a heparin or saline lock. The patientreturns to the blood drawing chair to receive their next series ofinsulin pulses. In the preferred embodiment, the subsequent insulinpulses must be covered by supplying glucose by mouth or other means. Thetotal time of the preferred procedure is approximately 6-7 hours.

[0014] In the preferred embodiment, two successive days of threetreatments are performed with a new patient. In the preferredembodiment, the above is repeated once a week. For patients who need amore intensive approach, it is preferable the procedure be repeated 3 ormore times, including continuously each week until the desired clinicaloutcome is achieved.

[0015] In the non-diabetic patient more glucose may be required than inthe diabetic patient, but the other parameters would remain the same,including the need for a pulse delivery.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The following description is provided to enable any personskilled in the art to use the invention and sets forth the best modepresently contemplated by the inventor of carrying out his invention.Various modifications, however, will remain readily apparent to thoseskilled in the art, as generic principles of the present invention havebeen defined herein.

[0017] The present invention is a system and method capable of improvingthe entire metabolic process and through its multiplicity of effects onneurovascular reactivity, intraglomerular pressure and hemodynamics,arresting the progression of overt diabetic nephropathy, improvingintraglomerular hemodynamics, and thus arresting the progression ofdiabetic nephropathy and therefore reducing the risk of development ofESRD. The current invention is a system and method of treating of kidneydisease using insulin pulses to a patient utilizing a ChronicIntermittent Intravenous Insulin Therapy to achieve the slowing,stopping or reversing of kidney disease in both diabetic and nondiabeticpatients.

[0018] The preferred embodiment of the invention is a system and methodof delivering insulin pulses to a patient utilizing a ChronicIntermittent Intravenous Insulin Therapy. The preferred embodiment ofthe treatment system comprises a means for determining a respiratoryquotient of a patient, a liquid or food containing glucose, anintravenous site, and a means of delivering a pulse of insulin at aregular interval of time.

[0019] The preferred means for determining a respiratory quotient of apatient is a SENSORMEDIC METABOLIC MEASUREMENT CART, however anyinstrument capable of measuring the respiratory quotient may be used.The respiratory quotient is defined as the ratio of carbon dioxideproduced to oxygen consumed by the patient.

[0020] The liquid or food containing glucose is consumed by the patientto prevent the patient from becoming hypoglycemic. The preferred liquidor food containing glucose is GLUCOLA, but any similar type of liquid orfood containing glucose may be given to the patient.

[0021] The preferred means of insulin delivery would be an infusiondevice capable of providing pulses of insulin on a prearranged interval,so long as there is sufficient glucose in the blood to keep the patientfrom becoming hypoglycemic. It is also preferable that the infusiondevice is capable of delivering the pulses of insulin in as shortduration of time as possible, without adversely affecting the vein atthe site of infusion is used. The preferred infusion device is theBIONICA MD-110. However, less accurate devices may deliver the pulsesand achieve the needed infusion profile of approximately six minutes.

[0022] In the preferred embodiment, a temporary or permanent intravenousaccess site located in the body, forearm or hand of the patient, wherebyinsulin is provided by intravenous pulses in a highly accurate manner,however any type of similar temporary or permanent intravenous accessmay be used. Currently, a 23 gauge catheter is inserted in to a hand orforearm vein. The amount of insulin is tailored to achieve more normalmetabolic function of the kidney. The metabolic function is measured bystabilization or decrease in 24-hour urinary protein excretion orstabilization or increase in creatinine clearance. Type 1 diabeticpatients receive 20-35 milliunits of insulin per kilogram of body weightper pulse and type 2 diabetic patients receive 70-200 milliunits ofinsulin per kilogram of body weight per pulse. During periods ofnon-use, the intravenous site is preferably converted to a heparin orsaline lock.

[0023] The preferred embodiment of the method of delivering insulinpulses to a patient utilizing Chronic Intermittent Intravenous InsulinTherapy is as follows. On the morning of the procedure, the patient ispreferably seated in a blood drawing chair and a 23 gauge needle orcatheter is preferably inserted into a hand or forearm vein to obtainvascular access. However, any system of such access may accomplish theneeded result, including indwelling catheters, PICC lines andPORTACATHs. After a short equilibration period the patient is asked tobreathe into an instrument which measures the patient's respiratoryquotient. Equilibrium is achieved when consecutive measurements of therespiratory quotient, at least 5 minutes apart, are the same. Inpractice the equilibration period was thirty minutes, however any periodof time that allows patient to establish a steady baseline, may be used.It is preferable that a SENSORMEDIC METABOLIC MEASUREMENT CART is usedto measure the respiratory quotient, however, any presently known modelmanufactured by any presently known supplier of instruments capable ofmeasuring a respiratory quotient may be used.

[0024] After the RQ is obtained, the patient is asked to consume aliquid or food containing glucose. The amount of glucose given to thepatient ranged from 60 to 100 grams, however the amount of initialglucose given to the patient may vary. A pulse of insulin is thenadministered intravenously on a regular interval of time until themeasured RQ shows improvement, as indicated by a RQ of 0.90 or greater.The usual interval of time was every six minutes, however, other regularintervals of time may be used. Improvement in RQ is generally achievedwithin one hour, however, the time required for RQ improvement may beshorter or longer than one hour.

[0025] The insulin/glucose phase is followed by a rest period of usuallyone hour. The rest period allows the elevated insulin levels to returnto baseline. The entire procedure is repeated until the desired effect,RQ greater than 0.90, is achieved. The preferred method of insulindelivery would be providing pulses of insulin on a prearranged interval,so long as there is sufficient glucose in the blood to keep the patientfrom becoming hypoglycemic. In order to determine the progress of thepatient, the RQ is measured every hour and blood glucose levels arechecked every thirty minutes by any means which shows that the patientis not becoming hypoglycemic.

[0026] Once the insulin pulses have been administered and the patientshows RQ improvement as indicated by a RQ of 0.90 or greater, thepatient is provided a rest period. During the rest period the patient isallowed to move around until the next series of insulin pulses areadministered. During the rest period the IV site is preferably convertedto a heparin or saline lock. The total time of the procedure isapproximately 6-7 hours.

[0027] The amount of insulin is tailored to achieve more normalmetabolic function of the kidney. The stabilization or decrease in24-hour urinary protein excretion or the stabilization or increase increatinine clearance measures metabolic function. Type 1 diabeticpatients receive 20-35 milliunits of insulin per kilogram of body weightper pulse and type 2 diabetic patients receive 70-200 milliunits ofinsulin per kilogram of body weight per pulse.

[0028] Usually with a new patient two successive days of threetreatments are performed the first week. For continuing patients theprocedure is performed once a week. For patients who need/require a moreintensive approach, the procedure may be repeated 3 or more times,including continuously, each week until the desired clinical outcome isachieved. The intensive approach is designed for patients whose 24-hoururinary protein excretion is unchanged or increases or whose creatinineclearance continues to fall. The desired clinical outcome is a decreasein urinary protein excretion in a 24-hour period or the stabilization ofthe fall or increase in creatinine clearance.

[0029] In the non-diabetic patient more glucose may be required than inthe diabetic patient, but the other parameters would remain the same,including the need for pulse delivery.

[0030] The following non-limiting example is given by way ofillustration only.

Example 1

[0031] The inventor hypothesized that the Chronic IntermittentIntravenous Insulin Therapy (CHIT) procedure, through its multiplicityof effects on neurovascular reactivity, intraglomerular pressure, andhemodynamics, may arrest the progression of overt diabetic nephropathy,improve intraglomerular hemodynamics, and thus arrest the progression ofdiabetic nephropathy and therefore reduce the risk of development ofESRD.

[0032] These results have been confirmed in a multi-center, long-term(37 months) retrospective longitudinal study of 31 patients with type 1DM (Aoki TT et al, Endocrine Practice, 1999, 5:174-78). This studyindicated that CIIIT seems to arrest or appreciably reduce theprogression of overt diabetic nephropathy. Creatinine clearance remainedessentially unchanged [from 46.1±3.0 ml/min at baseline to 46.0±3.9ml/min at the end of the observation period], and substantialimprovement in the glycemic control (hemoglobin Alc levels declined from8.6±0.6 to 7.6±0.3% [P=0.0062] during the study period) in patients withtype 1 DM and diabetic nephropathy was found.

[0033] The preferred embodiments described herein are illustrative only,and although the examples given include many specificity's, they areintended as illustrative of only a few possible embodiments of theinvention. Other embodiments and modifications will, no doubt, occur tothose skilled in the art. The examples given should only be interpretedas illustrations of some of the preferred embodiments of the invention,and the full scope of the invention should be determined by the appendedclaims and their legal equivalents.

What is claimed is:
 1. A system for treating kidney disease in diabeticand non-diabetic patients through an intravenous site administering apulse of insulin to a patient comprising: a) a means for determining arespiratory quotient of the patient, b) a liquid or food containingglucose, the liquid or food containing glucose being consumed by thepatient, and c) a means for administering intravenously the pulse ofinsulin at a regular interval of time until the respiratory quotient is0.90 or greater.
 2. The system of claim 1 , wherein the intravenous sitefurther comprises a needle or catheter located in the patient's body,hand or forearm.
 3. The system of claim 1 , wherein the liquid or foodcontains 60 to 100 grams of glucose.
 4. The system of claim 1 , whereinthe means for administering the pulse of insulin is an intravenousinfusion device.
 5. The system of claim 1 , wherein the interval of timeis about six minutes.
 6. The system of claim 1 , wherein the pulse ofinsulin is tailored to achieve a more normal metabolic function of thekidney.
 7. The system of claim 1 , wherein the intravenous site isconverted to a heparin or a saline lock when the administration ofinsulin pulses has temporarily ceased between treatments.
 8. A methodfor treating kidney disease in diabetic and non-diabetic patientsthrough an intravenous site administering a pulse of insulin to apatient comprising the steps of: a) determining a respiratory quotientof the patient, b) having the patient consume a liquid or foodcontaining glucose, c) administering intravenously the pulse of insulinat a regular interval of time until the respiratory quotient is 0.90 orgreater, d) providing the patient a rest period, and e) repeating thesteps a-d three times.
 9. The method of claim 8 , wherein theintravenous site further comprises a needle or catheter located in thepatient's body, hand or forearm.
 10. The method of claim 8 , wherein theliquid or food contains 60 to 100 grams of glucose.
 11. The method ofclaim 8 , wherein the pulse of insulin is administered by an intravenousinfusion devise.
 12. The method of claim 8 , wherein the interval oftime is about six minutes.
 13. The method of claim 8 , wherein the pulseof insulin is tailored to achieve a more normal metabolic function ofthe kidney.
 14. The method of claim 8 , wherein the intravenous site isconverted to a heparin or a saline lock during the rest period.
 15. Themethod of claim 8 , wherein the rest period is one hour.
 16. The methodof claim 8 , wherein said steps a-e are repeated at least once a week.17. The method of claim 8 , wherein said steps a-e are repeated three ormore times a week.